Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids.

A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.

Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors.

Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.